P999: ROLE OF GENETIC VARIANTS IN PREDICTING EFFICACY AND/OR ADVERSE EVENTS OF ROPEGINTERFERON ALPHA-2B IN MPN PATIENTS: A RETROSPECTIVE ANALYSIS FROM AN ASIAN COHORT
Authors: Chih-Cheng Chen, Ming-Chung Kuo, Ying-Hsuan Wang, Sung-Nan Pei, Ming-Lih Huang, Chiu-Chen Chen, Cih-En Huang, Yi-Yang Chen, Lee-Yung Shih
Journal: HemaSphere (2023)

Topic: 15. Myeloproliferative neoplasms - Biology & Translational Research Background: Ropeginterferon alpha-2b (ROPEG) induces high complete hematological responses (CHR) and molecular responses (MR) in polycythemia vera (PV) patients. Studies have shown that some single nucleotide polymorphisms (SNPs) could serve as excellent markers in foretelling the treatment outcome of IFN-α in myeloproliferative neoplasms (MPN). However, most data originated from western countries, and there is a pressing need to identify response predictors in different ethnic populations. Aims: To provide guidance on personalized therapy, we explored into genetic polymorphisms to predict efficacy and adverse events in our ROPEG-treated MPN patients. Methods: Targeted sequencing by NGS on a Miseq instrument was performed to detect SNPs in 9 loci across three genes [IFNL4, IFN-γ, and inosine triphosphate pyrophosphatase (ITPA)]. The mutational profile was determined using SOPHiA Myeloid Solution™ panel (v 2, 51 genes) and subsequently analyzed with SOPHiA DDM platform software in pre- and post-treatment samples. Real time quantitative PCR was used to monitor JAK2V617F allele burden periodically. ELN response criteria for CHR was adopted to stratify patients into good responders (CHR1, if CHR was achieved within 1 year) or poor responders (non-CHR1). Owing to a high MR rate (89.5%) in our patients, we further reclassified them with stringing criteria. We categorized homozygously JAK2V617F-mutated cases achieving allele burden < 10% and heterozygously mutated cases attaining > 90% reduction as major MR (MMR) responders, the remainders as non-MMR responders. Results: In all, 21 patients were enrolled, including 15 PV, 1 essential thrombocythemia, 3 primary myelofibrosis (PMF), and 2 prefibrotic PMF. JAK2V617F was the driver mutation in 19 cases, whereas the remaining two patients had CALR-mutated and triple negative (TN) diseases, respectively. Rates of CHR1 and MMR rates were 70% and 47.4% in 20 and 19 evaluable cases, respectively. SNPs from both IFNL4 and IFN-γ genes were excluded from further analysis because of their low frequencies. Two ITPA SNPs [rs1127354 and rs6051702] were associated with responses. Genotype rs6051702 (A/C) predicted an inferior CHR1 rate, a finding further strengthened by co-existing rs1127354 (Fig. A), whereas rs1127354 (C/A) foretold a disappointing MMR rate (Fig. B). Interestingly, individuals carrying rs6051702 (A/C) also exhibited a higher likelihood of developing grade 2 or worse hepatotoxicity (Fig. C). Twelve patients harbored 19 additional somatic mutations in 12 genes, but the presence of these variants was not associated with either CHR1 or MMR. The changes of allele burden in driver mutations and co-existing mutations (selected cases) are depicted in Figs. D and E, respectively. Strikingly, complete eradication of co-existing mutants was achieved in three clones after ROPEG therapy: TET2 mutation (E971V fs*4) in patient 12, as well as KDM6AT1345A and STAG2L513I in patient 10. Clonal evolution was observed in two cases, both developed a new ASXL1 mutation (G646W fs*12). These two patients also had poor clinical response not achieving either CHR1 or MMR. Summary/Conclusion: In summary, the use of genetic polymorphisms (specifically ITPA SNPs) to predict efficacy and adverse events in our MPN patients treated with ROPEG shows promise in improving personalized treatment and patient outcomes. Approximately half of patients achieved MMR of JAK2V617F and loss of co-existing mutations could occur in a subset of MPN patients following ROPEG therapy.Keywords: Ropeg-Interferon, Single nucleotide polymorphism, Myeloproliferative disorder, Polycythemia vera